Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Research and clinical investigations in psychiatry largely rely on the de facto assumption that the diagnostic categories identified in the Diagnostic and Statistical Manual (DSM) represent homogeneous syndromes. However, the mechanistic heterogeneity that potentially underlies the existing classification scheme might limit discovery of etiology for most developmental psychiatric disorders. Another, perhaps less palpable, reality may also be interfering with progress-heterogeneity in typically developing populations. In this report we attempt to clarify neuropsychological heterogeneity in a large dataset of typically developing youth and youth with attention deficit/hyperactivity disorder (ADHD), using graph theory and community detection. We sought to determine whether data-driven neuropsychological subtypes could be discerned in children with and without the disorder. Because individual classification is the sine qua non for eventual clinical translation, we also apply support vector machine-based multivariate pattern analysis to identify how well ADHD status in individual children can be identified as defined by the community detection delineated subtypes. The analysis yielded several unique, but similar subtypes across both populations. Just as importantly, comparing typically developing children with ADHD children within each of these distinct subgroups increased diagnostic accuracy. Two important principles were identified that have the potential to advance our understanding of typical development and developmental neuropsychiatric disorders. The first tenet suggests that typically developing children can be classified into distinct neuropsychological subgroups with high precision. The second tenet proposes that some of the heterogeneity in individuals with ADHD might be "nested" in this normal variation.psychiatric disorders | research domain criteria | cognition | modularity | executive functions

Behavioral genetic investigations have consistently demonstrated large genetic influences for the core symptom dimensions of attention-deficit/hyperactivity disorder (ADHD), namely inattention (INATT) and hyperactivity (HYP). Yet little is known regarding potential similarities and differences in the type of genetic influence (i.e., additive vs. nonadditive) on INATT and HYP. As these symptom dimensions form the basis of the current Diagnostic and Statistical Manual of Mental Disorders subtype classification system, evidence of differential genetic influences would have important implications for research investigating causal mechanisms for ADHD. The current meta-analysis aimed to investigate the nature of etiological influences for INATT and HYP by comparing the type and magnitude of genetic and environmental influences each. A comprehensive literature search yielded 79 twin and adoption studies of INATT and/or HYP. Of these, 13 samples of INATT and 9 samples of HYP were retained for analysis. Results indicated that both dimensions were highly heritable (genetic factors accounted for 71% and 73% of the variance in INATT and HYP, respectively). However, the 2 dimensions were distinct as to the type of genetic influence. Dominant genetic effects were significantly larger for INATT than for HYP, whereas additive genetic effects were larger for HYP than for INATT. Estimates of unique environmental effects were small to moderate and shared environmental effects were negligible for both symptom dimensions. The pattern of results generally persisted across several moderating factors, including gender, age, informant, and measurement method. These findings highlight the need for future studies to disambiguate INATT and HYP when investigating the causal mechanisms, and particularly genetic influences, behind ADHD.

Research examining pubertal timing effects on psychopathology has emphasized that a subset of adolescents, particularly females, who experience early pubertal maturation relative to their peers appear to be at increased risk for psychopathology. The aims of the current meta-analysis were (a) to quantify the magnitude of early pubertal timing effects on psychopathology, (b) to examine potential moderators of pubertal timing effects (sex, psychopathology domain, sample composition, measurement method, and mean sample age), and (c) to examine findings in relation to hypotheses in the extant literature explicating differential pubertal timing effects for early versus late youth and males versus females. A systematic literature search was conducted in PubMed and PsycINFO databases and 101 articles met criteria for inclusion. Included studies reported a quantitative association between pubertal timing and higher-order broadband dimensions of psychopathology (i.e., internalizing, externalizing), and/or lower-order subdomains (i.e., distress, fear, antisocial behavior, substance abuse, eating pathology). Using meta-analytic methods, we estimated global effect sizes (Cohen's ds) for the association between pubertal timing and psychopathology. Adolescent sex did not moderate early pubertal timing effects on emotional and behavior problems. However, robust early pubertal timing effects emerged for both males and females across all domains of psychopathology that were small in magnitude (ds∼.20). Measurement method of pubertal timing, but not sample composition or mean sample age, significantly contributed to the heterogeneity of effect sizes across studies. Findings have implications for refinement of theoretical models of pubertal timing effects on psychopathology and highlight the importance of empirical work that can identify pathways which may link offset pubertal timing to psychopathology during adolescence. (PsycINFO Database Record

Background-Attention-deficit/hyperactivity disorder (ADHD) and low-level lead exposure are high-prevalence conditions among children, and studies of large populations have suggested that these conditions are related. We examine this relationship in children from a community sample exposed to average background levels of lead who have a diagnosis of ADHD that is established by clinical criteria.